Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia

Huang

et al. 2021

Cancer Cell Int

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Background T-cell lymphoma (TCL) is highly aggressive and has a poor prognosis; thus, it is worth exploring biomarkers that may predict clinical outcomes and investigate their potential role in developing targeted therapies. In this study, we characterized the mutation pattern of tumor necrosis factor-alpha-inducing protein 3 (TNFAIP3) and its role in the prognosis of TCL patients. Methods Coding sequence (CDS) mutations in TNFAIP3 in TCL patients was explored using exome-sequencing data from 79 patients in our center (Guangdong Provincial People’s Hospital, GDPH) and 544 samples from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Additionally, non-CDS mutations in TNFAIP3 in 41 TCL patients from our center (JNU) were investigated by polymerase chain reaction (PCR) and Sanger sequencing. Furthermore, non-CDS mutations in TNFAIP3 in 47 TCL patients from Gene Expression Omnibus (GEO) dataset were explored. Results In the COSMIC database, TNFAIP3 mutations in TCL patients were located in the CDS, and the overall mutation frequency was 2.2%. However, TNFAIP3 mutations were not detected in the CDS of any of the samples in our center’s datasets. Interestingly, non-CDS TNFAIP3 mutations were found in 14.6% and 4.3% of TCL patients in the JNU and GSE15842 dataset, respectively. Importantly, there was a clear trend showing that TCL patients with a TNFAIP3 mutation were associated with a longer 5-year restricted mean survival time (RMST) and favorable OS rate compared with those without a TNFAIP3 mutation in the JNU dataset [hazard ratio (HR) = 0.29, 95% confidence interval (CI) 0.07 to 1.31, P = 0.089]. Furthermore, TNFAIP3 mutations significantly correlated with T-cell large granular lymphocytic leukemia (T-LGLL) with a favorable prognosis in the JNU dataset (P = 0.002). Notably, the different mutation patterns of TNFAIP3 when comparing our center and the COSMIC datasets might be due to different ethnic and genetic backgrounds. Conclusions To the best of our knowledge, we for the first time describe that TNFAIP3 mutations in non-CDS regions are associated with favorable OS for TCL patients, which might be a potential biomarker for the prognostic stratification of Chinese TCL patients.

Section: Discussionmentioning

confidence: 99%

TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma

Huang

et al. 2021

Cancer Cell Int

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“…RNA was reverse transcribed into cDNA using the High‐Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA). qRT‐PCR was performed with a qRT‐PCR kit (TIANGEN, Beijing, China), and β‐actin was used as an internal control 24,27 . Relative expression levels were calculated as a 2 –ΔΔCt method.…”

Section: Methodsmentioning

confidence: 99%

“…qRT-PCR was performed with a qRT-PCR kit (TIANGEN, Beijing, China), and β-actin was used as an internal control. 24,27 Relative expression levels were calculated as a 2 -ΔΔCt method. The primers for qRT-PCR are shown in Table S2.…”

Section: Rna Extraction and Qrt-pcrmentioning

confidence: 99%

Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin–proteasome pathway

Journal of Leukocyte Biology

Nie

Huang

et al. 2022

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T‐cell malignancies, including T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T‐cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T‐cell cell lines and primary T‐ALL cells. We provide evidence that DSF exerts anticancer activity in T‐cell malignancies by targeting the NPL4‐mediated ubiquitin–proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin–proteasome pathway genes, anaphase‐promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non‐ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T‐ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1‐, 3‐, and 5‐year OS rates for patients with T‐cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T‐cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T‐cells via the NPL4‐mediated ubiquitin–proteasome pathway and offer a potential therapeutic option for T‐cell malignancies.

“…HGC-27 and SGC-7901 cells' viability was determined by cell counting kit-8 (CCK-8) assays (Dojindo, Japan). 21 The cells were seeded into 96-well plates at a density of 3,500 cells/well overnight and treated with serial concentrations of PB (5, 10, 20, 30, and 40 μM). Dimethyl sulfoxide (DMSO; Invitrogen, New York, California, USA) was used as a control.…”

Section: Cell Viability Assays and Morphology Observationmentioning

confidence: 99%

Physalin B inhibits cell proliferation and induces apoptosis in undifferentiated human gastric cancer HGC‐27 cells

Fang

Asia-Pac J Clncl Oncology

Yang

et al. 2021

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Background Physalin B (PB) from Physalis angulata L. (Solanaceae) is a naturally occurring secosteroid with multiple biological activities, including anti‐inflammatory and anticancer activity. However, PB's effects and mechanisms in human gastric cancer (GC) cells are not well characterized. Methods The undifferentiated GC cell line HGC‐27 and semi‐differentiated GC cell line SGC‐7901 were treated with PB. Cell counting kit‐8 (CCK‐8) and colony formation assays were performed to evaluate cell viability. Apoptosis and the cell cycle were assessed by Annexin V/PI and PI/RNase DNA staining assays, respectively, and Western blotting was used to evaluate the expression of a protein. Results PB significantly inhibited the proliferation of HGC‐27 cells in a dose‐ and time‐dependent manner. Moreover, PB induced G0/G1 cycle arrest and caspase‐dependent apoptosis of HGC‐27 cells. Cleaved caspases 8, 3, and 7, poly(ADP)‐ribose polymerase (PARP), and the cyclin‐dependent kinase (CDK) inhibitor p‐Chk2 was induced by PB in HGC‐27 cells, while the cell cycle‐related proteins cyclin D1, cyclin D3, CDK4, CDK6, cyclin E, and phosphorylated retinoblastoma tumor suppressor protein (p‐Rb) were downregulated in a dose‐dependent manner. Conclusions PB inhibits proliferation via cyclin‐dependent kinase and induces caspase‐dependent apoptosis in HGC‐27 cells, suggesting that PB might be a novel and effective agent for undifferentiated GC therapy.